The advent of highly active anti-retroviral therapy (HAART), which involves the use of three or more antiretroviral drugs, has led to a significant improvement in the care and survival of patients infect with HIV-1. In patients not infected with resistant strains of the virus. HAART typically results in a dramatic decrease in viral load often from levels of 10,000-100,000 RNA copies/mL of plasma to less than 50 copies/mL.
Given the dramatic effects of HAART, it was proposed that complete elimination of the virus might be possible within 2 to 3 years. However, even after long-term suppression of viral replication with HAART, the virus rapidly rebounds after therapy is discontinued. A key contributor to viral rebound appears to be a reservoir of latently infected cells, including CD4 memory T cells. The half-life of the latently infected population is quite long, and it is estimated that it would take over 60 years of HAART to eliminate this population. Therefore, life-long HAART would be required to control infection in patients
Retroviruses, including HIV-1, are RNA viruses that replicate through a DNA intermediate and integrate very efficiently into the genome of an infected cell, forming a provirus. Once the provirus is formed, it is maintained in the genome of the infected cell and transferred to daughter cells in the same fashion as any other genetic element within the cellular genome. Thus, the virus has the potential to persist if it infects long-lived cells such as memory T cells. It has been known since 1986 that HIV-1 can establish a latent infection in culture. It was found that a human T cell line infected with replication-competent virus could develop a latent infection in which the provirus was dormant but could be reactivated upon stimulation. Since then it has been established that a number of cytokines can reactivate latent proviruses.
The role that latency is playing in preventing clearance of the virus infection has become evident in recent years. Patients that had been successfully treated with HAART in which viral RNA was maintained at levels below 50 copies/mL in the plasma for years, experienced rapid virus rebound upon withdrawal of therapy. Moreover, it was found that after T cell activation, virus could be isolated from CD4 T cells taken from these patients making it clear that to eradicate the virus it will be necessary to eliminate the latently infected cells.
There have been attempts to flush the latent virus from infected individuals by nonspecific activation of T cells to “turn on” latent proviruses. As part of this approach, the patients remain on HAART to prevent new infections, and the infected cells from which the latent proviruses are activated should die due to cytotoxic effects of viral expression and/or because of targeting by the immune system which can recognize the cells once they begin to express the viral proteins. Agents that can dissociate latent virus activation from global T cell activation, however, are extremely rare. Thus, there remains a need for new drugs capable of selectively activating latent viruses.